1-and 2-benzimidazolyl-lower-alkylamidoximes, amidines-, and guanidines



United States Patent Ofifice 3,354,174 Patented Nov. 21, 1967 3,354,174 1- AND 2JEENZIMHDAZOLYL-LGWER-ALKYLAMI- DOXIMES-, AMlDINES-, AND GUANIDINES Malcolm R. Bell, East Greenbush, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 19, 1964, Ser. No. 345,846 7 Claims. (Cl. 260309.2)

. This invention relates to the field of amidoximes, amidines, and guanidines, their acid-addition salts, and to intermediates and processes therefor.

The compounds of the invention are represented by the general formulas:

wherein Ar is selected from the group consisting of hicyclie aromatic nitrogen heterocyclic radicals having fused five and six membered rings and containing from two to three ring nitrogen atoms which can be in any position of the two rings; 1-, 2-, and 3-indolyl (in the compounds of Formula Ia only); l-, 2-, and 3-indolinyl; 1-, 2-, and 3-pyrrolyl; 1-, 3-, and 4-pyrazolyl; 1-, 2-, and 4-imidazolyl; IO-phenothiazinyl; 5-( 10,1l-dihydro-5H dibenz [b,f]azepinyl) and S-(dibenzo [a,d] [1,4] cycloheptadienylidenyl); R is from one to three members of the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine, and iodine), lower-alkyl, lower-alkoxy, loweralkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, nitro, trifluoromethyl, methylenedioxy, benzyloxy, benzyl, isonitrosomethyl, or di-lower-alkylaminomethyl; R is a member selected from the group consisting of hydrogen, lower-alkyl, lower-alkanoyl, and hydroxy; R is a member selected from the group consisting of hydrogen and lower alkyl; R is a member selected from the group consisting of hydrogen, lower-alkanoyl, benzoyl, lower-alkyl, and benzyl; Y is selected from the group consisting of C H where m is an integer from 0 to 5, and, in the compounds of Formula 1a, hydroxy-lower-alkylene containing from one to five carbon atoms and having the hydroxy group attached to the carbon atom adjacent to the amidoxime group; Y is lower-alkylene containing from one to six carbon atoms; and n is one of the integeis l and 2.

When Ar represents a bicyclic aromatic nitrogen heterocyclic radical having fused five and six membered rings and containing from two to three ring nitrogen atoms which can be in any position of the two rings, it is preferably of the 4.3.0 bridged system and is attached to Y (or Y) through an atom of the five membered ring. An especially preferred group of said heterocyclic bicyclic radicals includes 1- and 3-(2-azaindolyl); 1-, 2-, and 3-(4-azaindolyl); l-, 2- and 3-(5-azaindolyl); 1-, 2- and 3-(6-azaindolyl); l-, 2- and 3-(7-azaindolyl); 1- and Z-benzimidazolyl; l-(l-H-benzotriazolyl); 2-(2-I-I-benzotriazolyl); and 3-(py1ido-[2,1-c] -s-triazolyl).

The compounds of Formula Ia where the lower-alkylene group, Y, is a hydroxy-lower-alkylene group having the hydroxy group attached to the carbon atom adjacent to the amidoxime group, have the structure:

Ra R1(Ar [Y"CH-( J-N 8H INOR4\R3 n where R R R R Ar, and n have the meanings given above, and Y" is C H where m is an integer from 0 to 4.

In the above general Formulas la, 11), and 10, when R represents lower-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl, or lower-alkylsulfonyl, or when R R or R represent lower-aikyl, the lower-alkyl moiety can be straight or branched and can contain from one to about four carbon atoms. Thus R R R and R represent, inter alia, methyl, ethyl, i-sopropyl, n-butyl; or R represents, inter alia, methoxy, ethoxy, isopropoxy, methylmercapto, ethylrnercapto, n-butylmercapto, methylsulfinyl, 'ethylsulfinyl, n-butylsulfinyl, methylsulfonyl, ethylsulfonyl, or n-butylsulfonyl.

When R represents benzyl or benzoyl, the benzene rings thereof can be unsubstituted or can hear one to three substituents of low molecular weight and of such nature that they do not interfere with or take part in the reaction. Examples of such substituents include halogen (including fluorine, chlorine, bromine, and iodine), lower-alkyl, lower-alkoxy, lower-alkylrnercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, trifiuoromethyl, methylenedioxy, benzyloxy and benzyl.

In the above general Formula Ia, when R and R are loWer-alkanoyl, they can be straight or branched and can contain from one to about four carbon atoms. Thus R and R represent, inter alia, formyl, acetyl, propionyl, and isobutyryl.

In the above general Formulas Ia, Ib, and 10, when Y and Y represent lower-alkylene, they can be straight or branched, and when the group Y in the compounds of Formula 10 is attached to a nitrogen atom of a heterocyclic group, is such that at least two carbon atoms separate the nitrogen atoms of the heterocyclic group and the guanidine group. The lower-alkylene group Y thus stands, inter alia, for methylene, 1,2-ethylene, Z-methylethylene, 1,3-propylene, 2-methyl-l,4-butylene, 1,6-hexylene; and the group Y thus stands, inter alia, for methylene, 1,2- ethylene, Z-methylethylene, 1,3-propylene, 2-methyl-1,4- butylene, and 1,5-pentylene.

The compounds of Formula Ia where R R and R are hydrogen are prepared by reacting an aryl-nitrile or an aryl-lower-alkanonitrile with hydroxylamine (suitably in the form of a hydrohalide salt) in an organic solvent inert under the conditions of the reaction and in the presence of a base, for example, alkali metal hydroxides, alkoxides or carbonates. A preferred base is an alkali metal carbonate, for example, potassium carbonate or sodium carbonate. Suitable organic solvents are methanol, ethanol, isopropanol, benzene, toluene, and the like. A preferred solvent is ethanol. The reaction is represented by the equation:

where R Ar, Y, and n have the meanings given above.

The aryl-lower-alkanonitriles of Formula II required as intermediates in the above-described procedure are prepared by a variety of methods. One method involves the direct alkylation of an aryl nucleus using an appropriate halo-l-ower-alkanonitrile. The alkylation can take place either on a heterocyclic nitrogen atom bearing a replaceable hydrogen atom, or it can take place on a carbon atom bearing an activated hydrogen atom. The former is illustrated by the preparation of a 1-( cyano-loweralkyl)indole which is produced when indole (or a substituted-indole) is reacted with a halo-loWer-alkanonitrile in the presence of an acid-acceptor. If alkylation of a ring carbon atom is desired, it may be necessary to carry out the alkylation indirectly, that is by reacting the halo-lower-alkanonitrile with a Grignard reagent. This latter method is illustrated by the preparation of a 3- indolyl-lower-alkanonitrile which is produced by reacting a halo-lower-alkanonitrile with a Grignard reagent formed from indole (or a substituted indole) and a loweralkyl magnesium halide.

A second method for the preparation of the aryl-loweralkanonitriles of Formula II in which the lower-alkylene group, Y, is 1,2-ethylene comprises reacting acrylonitrile with an aromatic compound having an activated hydrogen atom either attached to a carbon atom or to a heterocyclic nitrogen atom. The reaction in the former case generally takes place spontaneously on admixture of the aromatic compound with the acrylonitrile, but in the latter case, it is generally necessary to employ a strong base as catalyst, for example, potassium t-butoxide, sodium hydride, organo ammonium hydroxides, for example Triton B, and the like.

The aryl-loWer-alkanonitriles of Formula II in which the lower-alkylene group, Y, is 1,2-cthylene can also be prepared by the catalytic reduction of the correspondingBerylacry-lohitrile. The latter in turn are prepared by reacting an appropriate aryl carboxaldehyde with cyanoacetic acid under basic conditions and decarboxylating the resulting 3-aryl-2-cyanoacrylic acid over copper chromite.

Still another method for the preparation of the aryllower-alkanonitriles of Formula II where the lower-alkylene group, Y, is methylene comprises metathetical replacement of a tertiary amino group of a Mannich base with cyanide ion. This method is illustrated by the preparation of 3-cyanomethyl-7-azaindole from 7-azagramine. The reaction is generally carried out in an aqueous medium at the reflux temperature using equimolar amounts of an alkali metal cyanide and a mineral acid. A preferred reaction medium is aqueous dimethylformamide.

In some cases it is desirable to introduce the 1oweralkanonitrile side chain at the time of formation of the aromatic ring to which it is attached. Thus a cyanomethyl group is introduced at the 2-position of the benzimidazole nucleus by reacting o-phenylenediamine with ethyl cyanoacetate. The reaction is preferably carried out in the absence of a solvent.

The compounds of Formula Ia where R is loWer-alkyl and R is hydrogen, or where both R and R are loweralkyl, are prepared by reacting a hydroxamic chloride derivative of Formula 111 below, wherein R R Ar, Y, and n have the meanings given hereinabove, with a lower-alkylamine or a di-lower-alkylamine,'R R Nl-l. The compounds of Formula Ia where R is hydroxy and R is hydrogen or lower-alkyl are prepared by reacting a hydroxamic chloride derivative of Formula III below,

wherein R Ar, Y, R and n have the meanings given hereinabove, with hydroxylamine or an N-lower-a1kylhydroxylamine, R NHOH. These reactions are represented by the following equations:

R31: Rs 11 A preferred starting material of Formula 111 is one wherein R is benzyl. The products can then be debenzylated with hydrogen over a suitable catalyst, for example, palladium-on-charcoal or Raney nickel, to produce compounds of Formula Ia where R, is hydrogen.

The arylhydroxamic chloride-O-benzyl ethers or aryllower-alkylhydroxamic chloride-O-benzyl ethers of Formula 111 (R is CH C H are prepared by reacting the corresponding arylamidoXime-O-benzyl ether or aryllower-alkanoamidoxime-O-benzyl ether of Formula Ia, where R and R are hydrogen and R is benzyl, with an alkali metal nitrite in the presence of hydrochloric acid under diazotization conditions. The reaction is represented by the following equation:

where R Ar, Y, and n have the meanings given above.

The arylhydroxamic chlorides or aryl-lower-alkylhydroxamic chlorides of Formula III (R, is H) are prepared by the reaction of chlorine in chloroform with the corresponding aldoxime.

The compounds of Formula Ia where R, is lower-alkyl or benzyl are prepared by reacting the corresponding amidoxime, where R, is hydrogen, with an alkali metal hydride in a suitable organic solvent inert under the conditions of the reaction, for example, dimethylformamide, and reacting the resulting alkali metal salt with a loweralkyl halide or a benzyl halide. Alternatively, the alkali metal salt can be prepared by reacting the amidoxime with an alkali metal hydroxide in an aqueous or alcoholic medium, e.g. methanol, ethanol, or isopropanol. The

reaction is represented by the equation:

/R2 /R2 R1(Ar) YCN R1(Ar) YCN ll NOH R3 1: NOM R: n

where R R R R Ar, Y and n have the meanings given above, except that R is not hydroxy, and M represents an ion of an alkali metal.

The compounds of Formula Ia where R is loweralkanoyl are prepared by reacting the corresponding amidoxime ethers, where R.;, is lower-alkyl or benzyl and R is hydrogen, with a lower-alkanoyl halide. When it is desired to prepare the compounds of Formula Ia where R is lower-alkanoyl and R is hydrogen, it is necessary to carry out the reaction with the lower-alkanoyl halide using the amidoxime-O-benzyl ether (R is benzyl). Subsequent catalytic debenzylation afiords the compounds where R; is hydrogen.

The compounds of Formula Ia. where R, is loweralkanoyl or benzoyl and R is hydrogen or lower-alkyl are prepared by reacting the corresponding amidoxime with a lower-alkanoic anhydride or with benzoic anhydride, as the case may be, in the presence of a base such as pyridine. The reaction is preferably carried out in an excess of pyridine, as the solvent medium, and at a temperature in the range from about 0 C. to about 50 C.

The compounds of Formula Ia where Y is a hydroxylower-alkylene group with the hydroxy group attached to the carbon atom adjacent to the amidoxime group are prepared by reacting the corresponding cyanohydrin with hydroxylamine using the same conditions as described above for the preparation of the compounds of Formula 1a where Y is a single bind or lower-alkylene. The reaction is represented by the equation:

R1(Ar)[Y"OHCEN]u 112N011 R1(A1)[Y"-oH-o-NH2 OH NOH where R Ar, and Y", and n have the meanings given above.

The intermediate cyanohydrins are prepared by reaction of hydrogen cyanide with the corresponding aryl-loweralkanaldehyde.

The compounds of Formula 111 are prepared by reacting the corresponding arylnitrile or aryl-lower-alkanonitrile with a lower-alkanol in the presence of a mineral acid, for example hydrogen chloride, under anhydrous conditions and reacting the resulting imino ester with anhydrous ammonia in an anhydrous lower-alkanol. The method is represented by the following equations:

alkanol medium at the reflux temperature thereof. The reaction is represented by the equation:

where R Ar, Y, and n have the meanings given above, and Alk represents lower-alkyl.

The aralkylamines of Formula IV are prepared by catalytic hydrogenation of the corresponding aryl-alkanonitriles of Formula II.

The novel compounds of the instant invention are the bases of Formulas Ia, lb, and I and the acid-addition salts of said bases, and said acid-addition salts are considered to be the full equivalents of the free bases. The compounds of the invention in free base form are converted to the acid-addition salt form by interaction of the base with an acid. In like manner, the free bases can be regenerated from the acid-addition salt form in the conventional mannor, that is, by treating the salts with strong aqueous bases, for example alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates. The bases thus regenerated can then be interacted with the same or a different acid to give back the same or a different acidaddition salt. Thus the novel bases and all of their acidaddition salts are readily interconvertible.

It will thus be appreciated that Formulas Ia, Ib, and not only represent the structural configurations of the bases of my invention but each is also representative of the respective structural entity which is common to all of my respective compounds, whether in the form of the free bases or in the form of the acid-addition salts of the bases. I have found that by virtue of this common structural entity, the bases and their acid-addition salts have inherent pharmacodynamic activity of a type to be more fully described hereinbelow. This inherent pharma-codynamic activity can be enjoyed in useful form for pharmaceutical purposes by employing the free bases themselves or the acid-addition salts formed from pharmaceuticallyacceptable acids, that is, acids whose anions are innocuous to the animal organism in effective doses of the salts so that beneficial properties inherent in the common structural entity represented by the free bases are not vitiated by side-effects ascribable to the anions.

In utilizing this pharmacodynanic activity of the salts of the invention, I prefer of course to use pharmaceuticallyacceptable salts. Although water-insolubility, high toxicity, or lack of crystalline character may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water-insoluble or toxic salts can be converted to the corresponding pharmaceutically-acceptable bases by decomposition of the salt with aqueous base as described above, or alternatively they can be converted to any desired pharmaceutically-acceptable acid-addition salt by double decomposition reactions involving the anion, for example by ion-exchange procedures.

Moreover, apart from their usefulness in pharmaceutical applications, my salts are useful a characterizing or identifying derivatives of the free bases or in isolation or purification procedures. Like all of the acid-addition salts, such characterizing or purification salt derivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases by reaction of the salts with aqueous base, or alternatively can be converted to a pharmaceutically-acceptable acid-addition salt by, for example, ionexchange procedures.

It will be appreciated from the foregoing that all of the acid-addition salts of my new bases are useful and valuable compounds, regardless of considerations of solubility, toxicity, physical form, and the like, and are accordingly within the purview of the instant invention.

The novel feature of the compounds of the invention, then, resides in the concept of the bases and cationic forms of the new amidoximes, amidines, and guanidines, and not in any particularv acid anion associated with the salt forms of the compounds; rather, the acid anions, which can be associated in the salt forms, are in them selves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with bases. In fact, in aqueous solutions, the base form or water-soluble acid-addition salt form of the compounds of the invention both possess a common protonated cation or ammonium ion.

Thus the acid-addition salts discussed above and claimed herein are prepared from any organic acid, inorganic acid (including organic acids having an inorganic group therein), or organo-metallic acid, organic monoand polysulfonic and -sulfinic acids, organic phosphonic and phosphinic acids, organic acids of arsenic and antimony, organic heterocyclic carboxylic, sulfonic, and sulfinic acids, acidic ion-exchange resins, and inorganic acids of "any acid forming element or combination of elements. In addition, other salt-forming compounds which are acidic in their chemical properties but which are not generally considered as acids in the same sense as carboxylic or sulfonic acids are also considered to be among the numerous acids which can be used to prepare acidaddition salts of the compounds of the invention. Thus there is also comprehended acidic phenolic compounds and acidic compounds having activated or acidic hydrogen atoms, as for example, picrolonic acid, or barbituric acid derivatives having an acidic proton. Also comprehended as salt forming agents are so-called Lewis acids which lack a pair of electrons in the outer electron shell and react with basic compounds having an unshared pair of electrons to form salts, for example boron trifluoride.

Thus appropriate acid-addition salts are those derived from such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic aid, benzoic acid, 4-methoxybenzoic 7 acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, Z-pyridinecarboxylic acid, 3-

3 ethyl acetate mixture, and the combined organic extracts were taken to dryness. Recrystallization of the residue from ether afforded 3.8 g. of (7-aza-l-indolyl) acetonitrile, M.P. 81.883.8 C. (corn).

indoleacetic acid, quinic acid, sulfamic acid, methanesul- Examples tonic acid, isethionic acid, benzenesulfonic acid, p-toluene- The following compounds of Formula II in Table 1 sulfonic acid, p-aminophenylarsinic acid, phenylstibnic were prepared from an appropriate aromatic compound acid, phenylphosphinous acid, methylphosphonic acid, and chloroacetonitrile using the manipulative procedure phenylphosphinic acid, Amberlite XE66 resin, hydrodescribed above in Example 1. The melting points are fluorlc acid, hydrochloric acid, hydrobromic acid, hyuncorrected unless noted otherwise.

TABLE 1 Example B1 A1 Y n M.P./Orystd. from 2 H 1,3-(7-azaindolyl) CH2 2 125.0126.5 0. (com) benzene] isopropanol.

3 H l-indolyl OH: 1 75.577.0G.cyc1ohexane.

4 3-011 .d0 CH2 1 5 2'01 IO-phenothiazinyl CH2 1 120-122 0. (corn) ethanol.

6 H l-benzimidazolyl CH2 1 136-1370 C. benzene.

driodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyani-c acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifiuoride, and the like.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Pharmacological evaluation of the compounds of Formulas la, Ib, and Te has demonstrated that they lower the blood pressure in dogs and rats thus indicating their usefulness as hypotensive agents.

The compounds can be prepared for use by dissolving under sterile conditions a salt form of the compounds in water (or an equivalent amount of a non-toxic acid if the free base is used), or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for use by injection. Alternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administration or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like. Still further the compounds can be formulated for oral administration in aqueous alcohol, glycol, or oil solution or oil-water emulsions in the same manner as conventional medicinal substances are prepared.

The chemical structures of the compounds of the invention are established by their mode of synthesis and are corroborated by the correspondence between calculated values for the elements and values found by chemical analysis.

The following examples will further illustrate specific embodiments of the invention without the latter being limited thereto.

PREPARATION OF THE INTERMEDIATES Example 1 (7-aza-1-indolyl)acetonitrile [11: R is H; Y is CH Ar is 7- aza-1-indolyl; n is 1].

To a stirred solution of 5.9 g. (0.05 mole) of 7-azaindole in m1. of hot dimethylformamide was added 1.2 g. (0.05 mole) of sodium hydride in mineral oil. When hydrogen evolution had ceased, a solution of 3.77 g. (0.05 mole) of chloroacetonitrile in Srnl. of dimethylformamide was added over a period of fifteen minutes. The reaction was stirred at room temperature for two hours, and taken to dryness in vacuo. The residue was suspended in water and ether, extracted with a benzene/ Example 7 [3-(2-cyan0ethyl)-7-aza-1-ind0lyl]acetonitrile [11: R is H; Ar is 1,3-(7-azaindolyl); Y is CH (1-position) and (CH (3-position); n is 2].

A solution of 29.0 g. (0.17 mole) of f3-(3-indolyl)- propi-onitrile in 175 ml. of dimethylformamide was treated with 7.75 g. (0.32 mole) of sodium hydride in mineral oil. When hydrogen evolution had ceased, the mixture was treated with chloroacetonitrile and allowed to stand for two days. The mixture was carefully de composed with water, taken to dryness in vacuo, and the resulting oil suspended in water and extracted with ether. The organic extracts were taken to drynms and the residue extracted with hot cyclohexane. The residue from the cyclohexane extraction was dissolved in ether, washed once with aqueous sodium carbonate, once with water, and the solution evaporated to dryness. The residue, on recrystallization once from benzene/ethanol and once from ethanol alone, afforded 9.02 g. of [3-(2-cyanoethyl)-7-aza-1-indolyl1aceto-nitrile, M.P. 106.5l08.0 C. (uncorn).

Example 8 6-(3-indolyl) valeronitrile [11: R is H; Ar is 3-indolyl; Y is (CH n is 1].

A mixture of 5.2 g. (0.215 mole) of magnesium turnings suspended in ether was treated with a solution of 28.4 g. (0.20 mole) of methyl iodide in ether. The resulting mixture was treated with a solution of 23.4 g. (0.20 mole) of indole in ether, and the solution was refluxed for about thirty minutes. The mixture was then cooled in an ice bath and treated rapidly with a solution of 32.4 g. (0.20 mole) of fi-bromovaleronitrile in ether. The mixture was stirred in an ice bath for about two and one-half hours and then refluxed for eighteen hours. The mixture was then treated with aqueous ammonium chloride solution, and the organic layer was separated and washed three times with water, once with sodium bicarbonate, twice again with water, and taken to dryness giving 40.4 g. of a red-brown gum. Fractionation of the latter in vacuo and collection of the fraction boiling at -158" C./0.0003 mm. gave 14.9 g. of crude product which was recrystallized once from ethanol/pentane and once from ethyl acetate/hexane to give 10 g. of 6-(3-indolyl)-valeron-itrile, M.P. 64.065.8 C. (corn).

Examples 912 The following compounds of Formula II in Table 2 were prepared from an appropriate indole and an appropriate w-bromo-l-ower alkanonitrile using the manipulative procedure described above in Example 8. The melting points are uncorrected unless noted otherwise.

TABLE 2 Example R; I Ar Y I n I M.P./Orystd. from 9 H 3-ind0lyl (C1105 l 4liil 44.0 0. (corn) ethyl acetate} exaue.

10 Z-CHa 1 B-P. 152-5 C./0.0007 mm.

11 5.6-0 (EH 0 1 l68l69'.5 C. benzene.

12 5,6-di-OH3O 1 132133.5 C. benzene.

Example 13 f3-(3-ind0lyl)pr0pi0nitrile [11: R is H; Ar is 3-indolyl;

Y is (CH n is 1].

A mixture of 117.2 g. (1.0 mole) of indole, 212 g.

(4.0 mole) of acrylonitrile, 2.0 g. of cupric acetate, 3.0

125 ml. of benzene was added 17 ml. of acrylonitrile. The mixture was stirred for three hours, diluted with ethyl acetate, washed with water, and the organic layer dried and taken to dryness giving 36.1 g. of a yellow oil which was distilled in vacuo. The fraction boiling at 101-102 C./0.08 ml. was collected giving 33.1 g. of fi-(7-aza-l-indolyl)propionitrile. The free base, dissolved in dry ether, was treated with hydrogen chloride in conventional manner giving ,8-7-aza-1-indolyl)propionitrile in the form of its hydrochloride salt, M.P. 151.0 152.0 C. (corn).

Examples 17-22 The following compounds of Formula II in Table 3 were prepared from an appropriate aromatic compound and acrylonitrile using the manipulative procedure described above in Example 16. The melting points are uncorrected.

TABLE 3 Ex. R Ar Y n M.P./Crystd. from- 17 H CHzCHz 1 B.P. l50.3152.0 C./0.94 mm. 18 CH2CH2 1 84S5 C. ethyl acetate/hexane. 19". 81338;? 1 82-88" etgaiiol.

2 2 9 96 .et y acetate/hexane. 21 CHzCHz 1 188.5-190" C. ethyl acetate.

CH2CH2 1 100-104 C.

0.7 g. of cupric acetate using the manipulative procedure Example 23 described above in Example 13. The crude material was purified by distillation in vacuo, and the fraction boiling at 159167.0 C./ 0.25 mm. was collected as product. The latter was recrystallized from an ethyl acetate/ hexane mixture giving 29.6 g. of ,6-(2-methyl-3-indolyl)propionitrile, M.P. 81-82 C. (uncorr.).

Example 15 fl-[Z-methyl I-Z-cyanoethyl) 3-incl0lyl]propionitrile [11: R is 2-CH Ar is 3-indolyl; Y is (CH (1- and 3-positions); n is 2].

To a slightly warm solution of 65.5 g. (0.50 mole) of Z-methylindole and 0.5 g. of powdered potassium hydroxide in 65 ml. of t-butyl alcohol was added dropwise, over a period of forty-five minutes, 29.2 g. (0.55 mole) of acrylonitrile while maintaining the temperature below 55 C. When addition was complete, the mixture was stirred for one half hour, then treated with 1.0 ml. of glacial acetic acid, diluted with ether, washed with water, and filtered to obtain 12.7 g. of crude product. The ether layer from the filterate was separated, taken to dryness, and the residual oil distilled in vacuo up to 185 C./ 1.13 mm. The heel from the distillation was triturated with methanol to give 5.05 g. of product. Recrystallization from ethyl acetate of the 12.7 g. crop of crude product ailorded an additional 4.50 g., thus giving a total yield of 9.55 g. of S-[Z-methyl-l- (Z-cyanoethyl)-3-indo1y1] propionitrile, MP. 148.5150.0 C. (uncorr.).

Example 16 ,6-(7-aza-1-ind0lyl)pr0pi0nitrile [11: R is H; Ar is 7- aza-l-indolyl; Y is (CH n is 1]. To a solution of 31 g. (0.26 mole) of 7-azaindole and about 1 g. of powdered potassium hydroxide in fl-(7-zrza-3-indolyl)propionitrile [11: R is H; Ar is 7-aza-3-indo1yl; Y is (CH n is 1].

A solution of 44.5 g. (0.24 mole) of 3-dimethylarninomethyl-7-azaindole, 36 g. (0.24 mole) of hexamethylenetetramine, and 190 ml. of 66% propionic acid was filtered and added, over a period of one hour, to a refluxing solution of 36 g. (0.24 mole) of hexamethylenetetramine in ml. of 66% propionic acid. The combined mixture was heated under reflux for two hours, diluted with 750 ml. of water, cooled, and after standing for three hours, the solid which had separated was collected, washed with water, and dried to give 17.2 g. of 7-aZa-3-indo1ylcarboxaldehyde, M.P. 214217 C. (uncorr.).

The latter (0.118 mole) was dissolved in 600 ml. of ethanol along with 11.0 g. (0.13 mole) of cyanoacetic acid and 13.7 g. (0.16 mole) of piperidine and refluxed for forty minutes. The reaction mixture was taken to dryness, the residue dissolved in aqueous sodium bicarbonate-sodium hydroxide solution, extracted with ether, and acidified to pH 6 with acetic acid. The solid which separated was collected, washed with water, and dried giving 22.5 g. of fl-(7-aza-3-indolyl)-a-cyanoacrylic acid, M.P. 250255 C. (uncorr.).

The latter (0.105 mole) was dissolved in 300 ml. of a eutectic mixture of diphenyl and diphenyl oxide. One gram of copper chromite was added, and the mixture was heated under reflux for twenty minutes, filtered, cooled, and extracted with 1:3 hydrochloric acid. The acid extracts were washed with ether, charcoaled, filtered, basified with aqueous sodium hydroxide, and the solid which separated was collected and dried giving 10.2 g. of crude product, M.P. 225240 C. (uncorr.). Recrystal- 1 l. lization from acetonitrile afforded 5.1 g. of B-(7-aza- 3-indolyl)acrylonitrile, M.P. 246-257 C. Further recrystallization from acetic acid/Water gave 1.93 g. of material having M.P. 256259 C. (uncorr.).

The latter (0.011 mole) was suspended in ethanol and reduced with hydrogen over a palladium-on-charcoal catalyst, reduction being complete in about twenty minutes. The reaction mixture was filtered, the solvent removed in vacuo, and the residue recrystallized twice from benzene giving 1.14 g. of B-(7-aza-3-indo1yl)propionitrile, M.P. 170.0-172.0 C. (corr.).

Example 24 (4-chlor0-3-ind0lyl)acetonitrile [II: R is 4-Cl; Ar is 3-indolyl; Y is CH n is 1].

A solution of 10.7 g. (0.032 mole) of 4-chloro-3- dimethylaminomethylindole methyl methosulfate and 4.8 g. (0.08 mole) of sodium cyanide in 100 ml. of water was heated gently on a steam bath for one hour. After standing overnight, the aqueous mixture was saturated with sodium sulfate and extracted with methylene dichloride. The combined organic extracts were taken to dryness, and the residual yellow solid recrystallized twice from benzene giving 2.36 g. of (4-chloro-3-indolyl-acetonitril'e, M.P. 132.6-134.6 C. (corn).

Example 25 (Z-m-elhyl-7-aza-3-indolyl)acetonitrile [Hz R is 2-CH Ar is 7-aza-3-indolyl; Y is CH n is 1].

A mixture of 9 g. (0.05 mole) of 3-dimethylaminomethyl-2-methyl-7-azaindole and 11.2 g. (0.23 mole) of sodium cyanide in 11.3 ml. of Water was treated dropwise with stirring and warming with 18.9 ml. of concentrated hydrochloric acid. The mixture was warmed for six hours, cooled, and the pale yellow solid which had separated was collected, dried, and recrystallized from ethanol giving 11.1 g. of (2-methyl-7-aza-3-indolyl)- acetonitrile, M.P. 200.8-204.2 C. (corn).

Example 26 (7-aza-3-indolyl)acetonitrile [11: R is H; Ar is 7- aza-3-indolyl; Y is CH n is 1] was prepared from 5.25 g; (0.03 mole) of 3-dimethylaminornethyl-7-azaindole, 7.38 g. (0.15 mole) of sodium cyanide, 12.5 ml. (0.15 mole) of concentrated hydrochloric acid, and 750 ml. of water using the manipulative procedure described above in Example 25. The crude product was recrystallized from benzene giving 0.54 g. of (7-aza-3-indolyl)acetonitrile, M.P. 141.4-142.6 C. (corn).

Example 27 (Z-benzimidazolyl)acetonitrile (II: R is H; Ar is 2- benzimidazolyl; Y is CH n is 1].

A mixture of 25 g. (0.23 mole) of o-phenylenediamine and 40 g. (0.35 mole) of ethyl cyanoacetate was heated at 180-183 C; for thirty minutes, cooled, washed with ether, and the ether-insoluble material was collected and recrystallized from water giving 9.5 gof (2-benzimidazolyl)acetonitrile, M.P. 206-209 C. (uncorr.).

Example 28 3-cyan0-7-azaind0le [11: R is H; Ar is 7-aza-3-indoly1; Y' is single bond; 11 is 1].

A mixture of 16.8 g. (0.115 mole) of 7-aza-3-indolylcarboxaldehyde, 20.0 g. (0.29 mole) of hydroxylamine hydrochloride, and 29.0 g. (0.29 mole) of sodium acetate trihydrate in 140 ml. of acetic acid was refluxed with stirring overnight, cooled, filtered, and the filtrate taken to dryness. The residue was slurried with water, filtered, and dried giving 11.8 g. of 3-cyano-7-azaindole, M.P. 249- 252 C. (uncorr.).

Example 29 (I-methyl-7-aza-3-indolyl)acetonitrile [11: R is 1- CH Ar is 7-aza-3-indolyl; Y is CH n is 1].

A suspension of 9.5 g. (0.21 mole) of sodium hydride in 500 ml. of dimethylformarnide was treated with 31.4 g. (0.02 mole) of (7-aza-3-indolyl)acetonitrile. When hydrogen evolution had ceased, the mixture was treated with 13.1 ml. (0.2 mole) of methyl iodide dissolved in a small amount of dimethylformamide over a period of about ten minutes. The reaction mixture was allowed to stand at room temperature for one week, diluted with 300 ml. of water and extracted with ether. The combined extracts were taken to dryness and the residue recrystallized from hexane giving 10 g. of (1-methyl-7 aza-3-indolyl) acetonitrile, M.P. 81-825. C. (uncorr.).

Example 30 (1 benzyl-7-aza 3 ind0lyl)acel0nitrile [I12 R is 1-C H CH Ar is 7-aza-3-ind'olyl; Y' is CH n is 1] was prepared from 31.4 g. (0.20 mole) of (7-aza-3-indolyl) acetonitrile, 9.5 g. (0.21 mole) of sodium hydride and 25.3 g. (0.20 mole) of benzylchloride in 500' ml. of dimethylformamide using the manipulative procedure described above in Example 29. The crude product was purified by chromatographing in ether on a column of 400 g. of activated magnesium silicate. The first liter of eluate was discarded, and the second liter was taken to dryness, and the residue recrystallized twice from benzene/hexane giving 14 g. of (1-benzyl-7-aza-3-indolyl) acetonitrile, M.P. 74.576 C. (uncorr.).

Example 31 4-chloro-2-cyanoindole [11: R is 4-Cl; Ar is 2-indolyl; Y is single bond, n is 1].

A mixture of 10.0 g. (0.052 mole) of 4-chloro-2-indolylcarboxamide and 50 ml. of phosphorous oxychloride was heated under reflux for thirty minutes until homogeneous, then cooled and poured into a mixture of 400 g. of ice and ml. of ammonium hydroxide. The mixture was rendered basic by addition of more ammonium hydroxide, cooled, and the solid which separated was collected and dried. Recrystallization of the crude product from benzene gave 5.3 g. of 4-chloro-2- cyanoindole, M.P. 167.4168.8 C. (corr.).

Examples 3260 By following one of the appropriate procedures given in Examples 1-31, using the appropriate starting materials, there can be obtained the compounds of Formula II listed below in-Table 4, where n in each case is 1.

TABLE 4 Ex- R Ar Y 32 Z-Br 5-(dibenzo[a,d][1,4] (CHm eycloheptadienylidenyl). as" 6-F 2-indolyl 0H a-ommornn H 7aza2-ind0lyl (CH H 4-aza-3-indolyl (CI-1 h H 5 aza-3-indolyl... (CH 1 H 6 aza-3-iudolyl 01103 H 2-pyrr0lyl CH(CH OH: H 3-pyrrolyl CH 1 H 1-pyrazolyl (011m H B-pyrazolyl. (CH 2 H -pyrazolyl. CH2) 2 H l-imidazolyl (CH-r) z H 2-imidazolyL. (CH2) 2 H 4-imidazolyl (CH 3 6 CH3S l-[lH-benzotriazolyl]- (CHm S-CHaSO 6-F Lbenzirnidazolyl (CH2) 2 6-CF3 2-benzimidaz0lyl (CH2) 2 H l-p yrrolyl (CH2) 2 Example ol H 2-(2-methyl-7-aza 3 indolyl) ethylamine dihydrochloride [IV R is 2-CH Ar is 7-aza-3-indolyl; Y is (CH n is 1].

Three grams (0.18 mole) of (2-methyl-7-aza-3-indolyl)-acetonitrile were added to about 125 ml. of absolute ethanol containing 15 ml. of concentrated hydrochloric acid. The mixture was reduced with hydrogen over 1.0 g. of platinum oxide catalyst at an initial pressure of 4-7 pounds p.s.i., reduction being complete in about an hour. The catalyst was removed by filtration, the filtrate was taken to dryness in vacuo, and the residual solid was recrystallized from isopropyl alcohol giving 35 g. of 2-(2-methyl-7-aza-3-indolyl)ethylamine dihydrochloride, M.P. 286-309 C. (uncorn).

Example 62 2-(7-aza-3-ind0lyl)ethylamine [IV:R is H; Ar is 7 aza-3-indo1yl; Y is (CH n is l] was prepared from 21.6 g. (0.14 mole) of (7-aza-3-iridolyl)acetonitrile in 40 ml. of methanol using a Raney nickel catalyst and a hydrogen pressure of about 1,100 pounds p.s.i. using the manipulative procedure described above in Example 61. There was thus obtained 18 g. of 2-(7-aza-3-indolyl)ethylamine, M.P. 124-133 C. (uncorr.).

Examples 63-I12- By following the manipulative procedure described above in Example 61, using an appropriate. aryl-loweralkanonitrile, there can be obtained the compounds of Formula IV listed below in Table 5.

. 14 PREPARATION OF A THE FINAL PRODUCTS Example 113 8- 7 -aza-3 -indolyl pro pionamidoxime dihydrochloride [111: R R R and R are H; Ar is 7-aza-3-indolyl; Y is (CH n is 1].

A solution of 15.3 g. (0.09 mole) of fi-(7-aza-3-indolyl) propionitrile, 12.4 g. (0.179 mole) of hydroxylamine hydrochloride, 38 g. (0.36 mole) of anhydrous sodium carbonate and 1,500 ml. of ethanol was refluxed and stirred overnight. The hot mixture was filtered, the filtrate taken to dryness, and the thick oily residue suspended in ethyl acetate, washed with water and aqueous sodium chloride, dried, and taken to dryness. The residue was dissolved in absolute ethanol, the solution was acidified with alcoholic hydrogen chloride and the solid, which separated on cooling, was collected, dried, and recrystallized from ethanol giving 3.5 g. of B-(7-aza-3-indolyl)propionamidoxime dihydrochloride, M.P. 238.5239.0 C. (corn).

Examples 114-140 The following compounds of Formula Ia (R R and TABLE 5 Ex. R1 Ar Y 'n.

7-aza-1-indolyl (CH2): 1 1,3-(7-azaindolyl) (CHzh 2 l-indolyl (CH1): 1 CH2): 1 2): 1 M 1 V 2)a 2 2)s Hzls 1 (CHM 1 CH2): 1 (CH2)3 2 ((3113):. 1 (1112):; 1 2): 1 2): 1 M 1 2): 1 H2 1 2): d0 r CH2): 1 2-indolyl CH2 1 5-(dibenzo[a,d] [1,41- (CH2)& 1

cycloheptadienylidenyl). 2indolyl (CH )3 1 Z-aZa-I-indolyl (CH2) 3 1 6C 3 2-aza-3-indolyl CH(CH3)CH2 1 3-CH=NOH 4-aza-1-indolyL (CHM. 3CHzN(CH3)2 5-aza-1-indolyl. (CH2)3 1 H (raza-l-indolyh CH (CH CHzCHz 1 H 4-aza-2-indoly1. CH2); 1 H 5-az a-Z-indolyl. CH2) 3 1 H 6-aza-2-indoly1 (C 2): H 7-aza2-indolyl (CHzh 1 H 4-aza-3-indolyl. (CH2)a 1 H 5-aza-3-i11dolyL (CHzla 1 H 6-aza-3-indolyL CH2)4 1 H 2-pyirolyl CH(CH3)CH2CH2 1 H 3-pyn'olyl CIT-12):: 1 H l-pyrazolyl (CHm 1 E B-pyrazolyL- (CH-m 1 H 4-pyrazo1yl CHM 1 H l-imidazolyL M 1 H Z-imidazolyL (CH2): 1

l-imidazol CH2); 1 6-OH3S l-[lHhenzotriazolyl] (CH2)a 1 G-OHKSO 2-[2H-benzotriazoly1] (CHM 1 108 3-CH3SO2 5-(10,11-dihydro-5H- (CH2)3 1 dibenzo[b,i]azepiny1). 109 fi-F l-benzimidazolyl (CH2); 1 110. 6CF3 Z-benzimidazolyl.-- 1 111 H V l-pyrrolyL, CH) 1 112 H 3-(pyrido-[2,1c]-s- (CH2); 1

V triazoy I TABLE 6 EX. R1

M.P./Crystd. from 1-CsH- CH Z'CHQ 7-aza-3-indoly1- 7a-za-3-indolyl 1 ,3- (7-azaindoly1) 7-az a-3-indolyl- 3 ind01yl 219.2220.8 C. ethanol. 175.4176.0 C. ethanol. 181.018l.6 C. ethanol. 129.5131.5 C. ethyl acetate. 175.0185.0 C. isopropanol/ Water. 206.8207.0 C. isopropanol/ water.

203. 0204.8 C. dimethylforrnarnide/water. 162.0-163.4 C. water. 128.21'34.0 C. ethyl acetate] hexane. 169.8170.4 C. ethanol/ether. 175.2177.8 C. ethyl acetate. 183.8184.'6 C.-ethan'0l. 1874-1880 C. ethanol. 138.5139.5 C. ethanol/water. 1342-1356 C. ethyl acetate. 107.6111.6 C. ethyl acetate/ hexane. 87.8-95.0 C. ethyl acetate/ hexane. 105.8107.2 C. benzene. 166.0167.6 C. ethyl acetate. 184.0185.6 C. ethanol.

152.4l52.7 C. ethanol.

90.0-91.0" C. benzene/hexane 1418-1490 C. benzene. 193.0l94.6 C. ethanol. 182.8183.8 C. ethanol. 219.0219.5 C. ethanol. 197.0199.0 C. ethanol.

1 Hydrochloride salt.

1 p-toluenesulfonatesalt.

By following the manipulative procedure described above in Example 113, there Was also prepared a-[l-(lH- benzotriazolyl)]acetarnidoxime, M.P. 207.6208.0 C. (corn) (prepared from a-[l-(lH-benzotriazolyl)]acetonitrile and hydroxylamine and recrystallized from methanol) and a a-[Z-(ZH-benzotriamlyl)]acetamidoxime, M.P. 178.0179.0 C. (corn) (prepared from a-[2-(2I-I- benzotriazolyl) ]acetonitrile and hydroxylamine and re crystallized from ethyl acetate).

Example 141 (7-aza-3-indolyl)acetamidoxime-O-acetate, M.P. 171.6-

172.6 C. (corr.).

(7-aza-3-ind0lyl)acetamidoxime-O-benzoute [Iaz Example 142 To a solution of 15 g. (0.08 mole) of 7-aza-3-indolyl) acetamidoxime in 100 m1. of pyridine was added, in small portions, 11.2 g. (0.08 mole) of benzoyl chloride While maintaining the temperature below 35 C. After standing overnight, the solution Was poured into 700 ml. of water and the gray precipitate that separated was collected, dried, and recrystallized from ethanol giving 11.4 g. of

(7-aza-3-ind0lyl)acetamidoxirne-O-benzoate, M.P. 176.6-

178.4 C. (corn).

By replacing the benzoyl chloride in the foregoing preparation by p-toluyl chloride, p-chlorobenzoyl chloride or 3-methoxybenzoyl chloride, there can be obtained the corresponding O-(p-toluate), O-(p-chlorobenzoate), or O- (3-methoxybenzoate), respectively, of (7-aza-3-ind0lyl) acetamidoxime.

Examples 143-] 76 By reacting an appropriate aryl-lower-alkanonitrile with hydroxylamine using the manipulative procedure described above in Example 113, there can be obtained the Compounds of'Formula Ia (R R and R are H) listed below in Table 7, where n in each case is l.

TABLE 7 Ex. R Ar Y 143- Z-Br 5-(dibenzo[a,d][1,4]- (CH1) eyclohepta I dienylidenyl) 144.- (5-1? 1 2-indolyl (CH2); 145. 6-1 2-aza-1-indolyL. (CH2) 2 63-0 Fa 2-aza-3-indolyL. CH(CH;) 3-CH=NOH 4-aza-1-indolyL. (CHM 3-CH1N (CHa)z 5-azar1-indolyL. (CH2); H G'flZfirl-llldOlYL. CH(CH3) CH2 H 4-azar2-indolyl (CH2) 1 H 5-aza-2indolyl (C H 2 H 6-aza-2-ind0lyl (CH1) 2 H 7-aza-2-indolyl (CH2): H 4.- (C1192 H 5-aza-3-indolyL. (CHM H 6-aza-3-indolyl. CH 3 H Z-pyrrolyl CH (CH CH2 H 3-pyrrolyl- CH2); 159-".-. H l-pyrazolyl... (CH2): 160. H B-pyraz (CHm 161. H 4-pyrazolyl... (CHgh 162. H l-imidazolyl.-- (CH2); 163 H 2-imidazolyl. (CHM 164. H 4in1idazolyl (CH2); 165. 6-CH S 1-[1H-benz0triaz0lyl]. (CH2); 166. 6-CH3SO 2-[2H-benzotriazolyl]- (CH1); 167 3-CH SO2 5-(10,11-dihydro-5H- (CHm dibenzo [b,f]azepinyl. 6-F l-benzimidazolyl (CHM 6-0 F; Z-benzimidazolyl (CHM H l-pyrrolyl (Cl-1m H 3-(pyrido-[2,1-c1-s- (CH2) 3 triazo y 172- H B-indolyl (CHm 173 H do (CH2)5 174". 2-6113 d0. (CHzh 175 4-01 --do CH2 176..." 4 Cl 2-ind0lyl Example 1 77 (7-aza-3-ind0lyl)acetamidoxime-O-benzyl ether [Iaz R R and R are H; R.,, is C H CH Ar is 7-aza-3-indolyl; Y is CH n is 1].

By reacting (7-aza-3-indolyl)acetamidoxime with benzyl chloride, 4-methylmercaptobenzyl chloride, 4- methylsulfonylbenzyl chloride, or 4-trifiuoromethylbenzy1 chloride, in the presence of sodium hydroxide, there can be obtained, respectively, (7-aza-3-indolyl)acetamidoximc-Obenzyl ether, -O-(4-methy1cercapto-benzyl)ether,

Example 178 18 Example 181 (7-aza-3-indolyl)-a-hydroxyacetam idoxime [Iaz R R R and R are H; Ar is 7-aza-3-indolyl; Y is CHOH; n is 1].

5 (7-aza-3-ind0lyl) acetamidoxime 0 methyl ether [Ia: d By reactlllg i 53 1? fil ig g 2 R R and R are H; R, is CH AT is 7-aza-3-indolyl; Y r0311 P an mac e.resu mg a y is n is 1] hydrm with hydroxylamlne usmg the manlpulatlve pro- By reacting (7 -aza-3 -indolyl)acetamidoxime with ig f f i l s"? 3 i l i l g g be methyl iodide in the presence of sodium hydroxide, there 10 O ame 0y y 'oxyac arm 0 1 can be obtained (7 aza 3 indolyl)acetamidoxime 0- Example 182 methyl ether (7-aza-3-indolyl')-N-aqetylacetamidoxime 0 acetate Example 179 [Iaz R and R are H, R and R are CH CO; Ar is 7-aza- 3-indolyl; Y is CH n is l]. -aza-3-ind0lyl)- y tamzdoxzm e [lat R1 15 By reacting (7 aza 3 indolyl)acetamidoxirne with and 4 are 2 and s are 2 5; 15 H2; 1S acetic anhydride in the presence of pyridine, using the y reacting the (7-aZa'3'iI1d01y1)acetamldoxlme manipulative procedure described above in Example 141, benzyl ether, described above In EXample With there can'be obtained (7-aza-3-indolyl)-Nacetylacetamisodium nitrite in the presence of hydrochloric acid at a d i O- t temperature from about 0 C. to 5 0., there can be 0b- Example 183 tained (7-aza 3 indolyl)acetohydroaminic chloride-O- benzyl ether. By reacting the latter with diethylamine, Zfffg g gggf f g it 31W??? R1 15 there can be obtained (7-aza-3-indolyl)-N,N-diethylacety znls Anhydrous hydrochloride was bubbled through a mixamldoxlme'o'benzyl ether ture of 3 1 (0 02 mole of (7-aZa-3-'nd0l l)a eto By reducing the latter with hydrogen over a palladium- 2 O than 1 d 50 1 M y f 5 on-charcoal catalyst, there can be obtained (7-aZa-3-in- 1 an 0 c on) 0 m or dol Ndieth lacetamidoxime about three hours while maintainlng the temperature y y around 0 C. and protecting the mixture from atmospheric moisture. The mixture was taken to dryness in vacuo, and Example 180 treated, while cooling, with a solution of 10 ml. of liquid ammonia in ethanol. The milky suspension was then y f y m acid f stirred at room temperature for'three hours, filtered, and 3 and 4 are 2 15 Ar 15 Y 18 the filtrate charcoaled and taken to dryness. The residual CH n is 1 gum was crystallized several times from ethanol giving y reactmg the 3 mdolyhacetohydroxamlc 1.84 g. of (7-aza-3-indolyl)acetamidine hydrochloride, chloride-O-benzyl ether described above in Example 179 y, 254,0 256 4 C with hydroxylamine, there can be obtained (7-aza-3-in Ex I 184 233 dolyl)-N-hydroxyacetamidoxime-O-benzyl ether. By reamp es ducing the latter with hydrogen over a palladium-on- By treating an appropriate aryl-lower-alkanonitrile with charcoal catalyst, there can be obtained (7-aza-3-ind0lyl)- anhydrous ethanolic hydrogen chloride, followed by treat- N-hydroxyacetamidoxime. ment of the resulting imidate ester with alcoholic ammo- Similarly, by replacing the hydroxylamine by N-methylnia using the manipulative procedure described above in hydroxylamine, there can be obtained (7aza-3-indolyl)- Example 183, there can be obtained the compounds of N-hydroxy-N-methylacetamidoxime. Formula Ib listed below in Table 8.

TABLE 8 Ex. R1 Ar Y n H 7aza-1-indoly1" OH: 1 H 1,3-(7-azaindolyl CH2 2 H l-indolyl CH2 1 3-CH3 -..-.do CH1 1 2-01 10-phenothiazinyl CH; 1 H 1benzimidazolyl CH1 1 E 1,3-(7-azaindolyl) 3 8 2 2-0113 (CHM 1 5,6-OCH3O CH: 1 sear-c1130 I I OH: 1 Ha (CH2): 2 7-aza-1-indolyl (CH1): 1 Z-CHa l-indolyl. (CHM 1 3-CH3 CH2): 1 5"C5H5CH2O d0 (CH2): 1 4-01 B-indolyl CH2 1 2-011; 7-aza 3-ind0ly1 CH1 1 H 1 1-CH3 ..---do 0H, 1 1-CnH5CH2 ----J1 CH2 1 4-01 2-ind0lyl 1 Z-Br 5-(dibenzo[a,d][1,4]- (Cum 1 cycloheptadienylidenyl) 2-indolyl 1 Z-aza-l-indolyl 1 2-aza 3-indolyl 1 4 aza-l-indolyl 1 5-aza-l-indolyl 1 (ram l-indolyl 1 4-aza-2-indolyl 1 5-aza-2-indolyl 1 6aza-2-indolyl 1 7-aza-2-ind0lyl 1 4-aza 3indolyl 1 5 aza 3-indolyl 1 6-aza-3-ind0lyl (CH2)3 1 2-pyrro1yl CH(CH;)CH1 1 3-pyrro1yl (CHm 21 Pharmacological evaluation of the compounds of Formula Ia has demonstrated that they lower the blood pressure in rats and mice; they possess psychomotor stimulant as well as depressant activities as evidenced by studies in mice using standard activity cages; and they possess sedative activity as shown by the potentiation of sleeping time in mice induced by ether, thiopental sodium, or hexobarbital sodium. These activities indicate their usefulness as hypotensive agents, tranquilizers, and sedatives.

Hypotensive activity data are given for representative compounds of Formula la in Table below where each of the compounds is identified by a number of the example above where its preparation is described. The activities are expressed in terms of the AED, i.e. the Average Efiective Dose. As used hereinafter, the abbreviations i.p., 12.0., and s.c. designate intraperitoneal, peroral, and subcutaneous administration, respectively.

TABLE 10.HYPOTENSIVE ACTIVITY Ex ample Activity 113 80 mg./kg. (s.c.) 114 40 mg./kg. (s.c.) 115 60 mg./kg. (s.c.) 116 mg./kg. (s.c.) 118 m.g./kg. (s.c.) 121 8 mg./kg. (s.c.) 122 5 mg./-kg. (s.c.) 123 20 mg./kg. (s.c.) 124 20- mg./kg. (s.c.) 125 20 mg./kg. (s.c.) 126 40 mg./kg. (s.c.) 127 10 mg./kg. (s.c.) 129 20' mg./kg. (s.c.) 132 5O mg./kg. (s.c.) 133 9 mg./kg. (s.c.) 138 80 mg./kg. (s.c.) 139 10 mg./kg. (s.c.)

Psychomotor depressant activity data are given for representative compounds of Formula Ia in Table 11 below. The activities are expressed in terms of the minimum eflective dose (MED) and of the percent decrease in motor activity.

TABLE 11 Example Activity 119 MED=300 mg./kg. (p.o.); 55%

121 MED=30O mg./kg. (p.o.); 65%

122 MED=300 mg./'kg. (p.o.); 59%

123 MED=100 mg./kg. (p.o.); 61%

133 MED=300 mg./kg. (p.o.); 78%

Certain of the compounds also possess psychomotor stimulant activity in mice as evidenced by their ability to increase the motor activity of mice in activity cages. Thus ,6 (S-benzyloxy-l-indolyl)propionamidoxime, described above in Example 132 was active at 12 mg./kg. (p.o.), producing a 178% increase in motor activity.

Other compounds possess sedative activity as evidenced by their ability to potentiate the sleeping time in mice induced by hexobarbital sodium. Thus the effective dose, ED of ,6-(2-chloro-10-phenothiazinyl)propionamidoxime, described above in Example 136, in potentiating the sleeping time of mice to which hexobarbital had been administered was found to be 455:8.7 ing/kg. (i.p.).

The compounds of Formula Ib have been found to possess hypotensive activity as determined in the renal hypertensive rat. Thus (7-aZa-3-indolyl) acetamidinehydrochloride, described above in Example 183, was found to have an Average Effective Dose, AED, of 8 mg./ kg. when administered subcutaneously in the renal hypertensive rat.

The compounds of Formula Ic have also been found to posses hypotensive activity as determined in the renal hypertensive rat. Thus 2-(7-aza-3-indolyl)ethylguanidine hydrobromide, described above in Example 235, was found to have an Average Effective Dose, AED, of 30 22 mg./kg. when administered subcutaneously in the renal hypertensive rat.

I claim: 1. A compound of the formula:

N OR4\R3 11 wherein Ar is a member of the group consisting of 1- and Z-benzimidazolyl; R is from one to three members of the group consisting of hydrogen, halogen, lower-alkyl, lower alkoxy, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro, trifluoromethyl, methylenedioxy, benzyloxy, benzyl, isonitrosomethyl, and di-loweralkylaminomethyl, R is a member of the group consisting of hydrogen, lower-alkyl, lower-alkanoyl, and hydroxy; R is a member of the group consisting of hydrogen and lower-alkyl; R is a member of the group consisting of hydrogen, lower alkanoyl, benzoyl, lower-alkyl, and benzyl; Y is a member of the group consisting of C H wherein m is an integer from 0 to 5, and hydroxy-loweralkylene of from one to live carbon atoms and having the hydroxy group attached to the carbon atom adjacent to the amidoxime group; and n is one of the integers 1 and 2.

2. A compound of the formula:

wherein Y is lower-alkylene of from one to five carbon atoms.

3. A compound of the formula:

wherein Y is loWer-alkylene of from one to five carbon atoms.

4. a-( l-benzi-midazolyl) acetamidoxime.

5. ot-(2-benzimidazolyl)acetamidoxime.

6. A compound of the formula:

wherein Ar is a member selected from the group consisting of 1- and Z-benzimidazolyl; R is from one to three members of the group consisting of hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylmencapto, loweralkylsulfinyl, lower-alkylsulfonyl, nitro, trifluoromethyl, methylenedioxy, benzyloxy, benzyl, isonitrosomethyl, and di-lower-alkylaminomethyl; Y is C H wherein m is an integer from 0 to 5; and n is one of the integers 1 and 2.

7. A compound of the formula:

wherein Ar is a member selected from the group consisting of 1- and Z-benzimidazolyl; R is from one to three members of the group consisting of hydrogen, halogen,

References Cited UNITED STATES PATENTS 2% i FOREIGN PATENTS 1,582 11/1962 France. 35/17134 11/1960 Japan. 38/6783 5/1963 Japan.

OTHER REFERENCES Migrdichian Organic Synthesis, v01. 1, pages 429-31, N.Y., Reinhold, 1957.

Gaynor et a1. 260564 .Mull et a1.: Jour. Amer. Chem. 800., vol. 80, pages Mikeska 260-564 10 3769-72 (1958).

Schaefer et' a1. 260564 Walker: 1 our. Amer. Chem. Soc., vol. 77, pages 3664-7 Urspr'ung' 260-309. 2 (1955).

zfigg i WALTER A. MODANCE, Primary Examiner. Cmpbell 260-310 15 H. I. MOATZ, N. TROUSOP, Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,354,174 November 21, 1967 Malcolm R. Bell It is hereby certified that error appears in the above numbered pate'nt requiring correction and that the said Letters Patent should read as corrected below.

Column 1, formula Ia should appear as shown below instea of as in the patent:

column 4, lines 12 to 17, the formulas should appear as shown below instead of as in the patent:

R (Ar) Y'C-NH2 R1 (Ar) Y'---- (:1

oca c a noca c a lines 43 to 48, the formula should appear as shown below instead of as in the patent:

column 9, line 49, for "1-2" read l-(Z column 11, lin 24 and 25, for "indolyl-acetonitrile" read indolylJacetonitrile column 12, TABLE 4, second column, line 3 thereof, for "61" read 6-I column 13 TABLE 5 fourth column, opposite Ex. 93, insert l column 15, line 36, for "and a a-[2 read and a-[Z column 16, TABLE 7,

fourth column, line 1 thereof, for "(CH read [CH UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,354,178 November 21, 196

William B. Dickinson It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, line 26, "N-methy1-N-4-" should read N- methyl-N-(4- Column 8, line 52, "N-[4-(3-pyrrolin-l-y1- 2-butynyl] -2pyrrolidinone" should read N-(4-pyrrolidino- 2-butynyl)-3-thiamorpholinone Column 9, line 12, "N4" should read N-[4- line 13, "N-[4-N-" should read N- [4-(N- Column 10, lines 18 to 20, the formula should appear as shown below:

CH CH R-CO-IiI-CH -CEC-CH -N lower alkyl CH CH Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, J Attesting Officer Commissioner of Patent 

1. A COMPOUND OF THE FORMULA:
 6. A COMPOUND OF THE FORMULA:
 7. A COMPOUND OF THE FORMULA 